MGMT promoter methylation prognostic biomarker for low-grade glioma

O⁶-methylgaunine-DNA-methyltransferase, or MGMT, promoter methylation appeared to be significantly associated with PFS and OS among patients with high-risk low-grade glioma, according to findings from a correlative analysis of the NRG Oncology/Radiation Therapy Oncology Group 0424 clinical trial.

This represented the first clinical trial-based evidence of the prognostic importance of MGMT promoter methylation among patients with grade 2 glioma.

“[These are] also the first data to highlight the test’s potential prognostic value beyond a standard molecular test currently used to help predict patient survival outcomes,” Erica H. Bell, PhD, assistant professor in the department of radiation oncology at The Ohio State University Wexner Medical Center, said in a press release.

Results from the NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9802 clinical trial indicated patients with high-risk low-grade glioma had improved OS when treated with the addition of procarbazine (Matulane, Leadiant Biosciences), lomustine (Gleostine, Corden Pharma) and vincristine to radiotherapy. However, the procarbazine, lomustine and vincristine regimen produced significant adverse events. As a result, temozolomide, a more tolerable agent, has been under investigation.

Initial reports from NRG Oncology/RTOG 0424 — a single-arm phase 2 clinical trial that investigated the combination of temozolomide and radiotherapy among patients with high-risk low-grade glioma — showed patients had a 3-year OS of 73.1%, which was significantly higher than the 54% rate among a historical control group treated with radiotherapy alone. However, results from MGMT analyses were unavailable at the time of that report.

In this analysis, Bell and colleagues evaluated MGMT methylation status and its association with survival outcomes to determine its prognostic significance. MGMT promoter methylation leads to epigenetic silencing of the MGMT gene and loss of protein expression, causing accumulation of DNA damage and increased sensitivity to temozolomide, according to the researchers.

“Identifying biomarkers — prognostic and predictive markers — is critical for personalizing care and giving patients the best quality of life and chances of longer survival. These tumors are tricky to treat because there is such a wide range of outcomes,” Arnab Chakravarti, MD, chair of radiation oncology at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital, and senior study author, said in the press release. “Some patients succumb to the disease within months, [whereas] others live years beyond their diagnosis. We need better methods of determining which patients are likely to have more aggressive tumors.”

Seventy-five (median age, 48 years; 56% men) of 129 eligible patients had MGMT status available, 76% of whom were methylated and 24% unmethylated.

Thirteen unmethylated patients (72.2%) had astrocytoma — as opposed to oligodendroglioma or mixed tumors — compared with 23 methylated patients (40.4%).

Univariate analyses showed a significant association between unmethylated MGMT promoter and worse OS (HR = 3.52; 95% CI, 1.64-7.56) and PFS (HR = 3.06; 95% CI, 1.55-6.04).

Median OS for unmethylated patients was 3 years (95% CI, 2.3-not reached), and median PFS was 2 years (95% CI, 0.9-4.9). The median OS and PFS was not reached among the methylated patients.

Multivariate analyses, without inclusion of IDH1/2 mutation status, maintained significance for OS (HR = 2.89; 95% CI, 1.31-6.38) and PFS (HR = 2.967; 95% CI, 1.48-5.96). The statistical significances persisted in multimarker multivariable analyses that included IDH1/2 mutation status for both OS (HR = 2.7; 95% CI, 1.02-7.14) and PFS (HR = 2.74; 95% CI, 1.19-6.33).

Small sample size of the overall study cohort, as well as the IDH-nonmutant population, posed a limitation that will be crucial for the future in defining whether MGMT promoter methylation adds prognostic value only to the IDH-nonmutant subgroup, researchers noted.

Despite these data, researchers noted identifying a subgroup that benefits from the addition of temozolomide to radiotherapy “remains elusive.”

“It is imperative that future clinical trials include molecular markers as stratification or eligibility criteria,” the researchers wrote. “Future analyses will include examining the prognostic significance of MGMT methylation with other known prognostic markers, such as the newly defined WHO subgroups (including 1p/19q codeletion status) with long-term follow-up data.” – by Melinda Stevens

Disclosure s : The authors report no relevant financial disclosures.